PGF{HD 3{B {331 {0 Analogs

ABSTRACT

This disclosure relates to prostaglandins of the PG3 series including PGE3, PGF3 , PGF3 , PGA3, and PGB3, to various analogs of those in racemic form, and to novel processes for making those. This disclosure also relates to certain fluorine and alkyl substituted analogs and certain acetylenic analogs of PGE3, PGF3 , PGF3 , PGA3, and PGB3 in both racemic and optically active form, and to processes for making those. These various analogs are useful for the same pharmacological purposes as the known optically active forms of PGE3, PGF3 , PGF3 , PGA3, and PGB3, including anti-ulcer, inhibition of platelet aggregation, increase of nasal patency, labor inducement, fertility control, and wound healing.

United States Patent [191 Axen [ Dec. 9, 1975 PGF B ANALOGS [73]Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Nov. 5, 1973 [21] Appl. No.: 412,801

Related US. Application Data [63] Continuation-in-part of Ser. No.ll2,032, Feb. 2, 1971, Pat. No. 3,775,462, which is acontinuation-in-part of Ser. No. 30,312. April 20, I970, abandoned.

[52] US. Cl. 260/468 D; 260/211 B; 260/242 B; 260/268 R; 260/243.65;260/326.2; 260/408; 260/410; 260/4lO.5; 260/410.9 R; 260/413; 260/424.9;260/439; 260/448 R; 260/50l.l; 260/50l.l5; 260/501.l7; 260/501.2;260/514 [51] Int. Cl. C07C 61/38; C07C 69/74 [58] Field of Search.....260/468 D, 514 D, 410.9 R, 260/413 [56] References Cited UNITED STATESPATENTS 3,514,383 5/1970 Beal et al. 204/158 3,767,695 l0/l973 Pike etal.... 260/468 3,804,880 4/1974 Bergstrom 260/468 FOREIGN PATENTS ORAPPLICATIONS 2,118.686 ll/l97l Germany ..260/468 747,348 9/1970 Belgium..260/468 Primary Examiner-Robert Gerstl [57] ABSTRACT This disclosurerelates to prostaglandins of the PG;, series including PGE PGF PGF B PGAand PGB to various analogs of those in racemic form, and to novelprocesses for making those. This disclosure also relates to certainfluorine and alkyl substituted analogs and certain acetylenic analogs ofPGE PGF PGF B PGA and PGB in both racemic and optically active form, andto processes for making those. These various analogs are useful for thesame pharmacological purposes as the known optically active forms of PGEPGF PGF B PGA and PGB including anti-ulcer, inhibition of plateletaggregation, increase of nasal patency, labor inducement, fertilitycontrol, and wound healing.

13 Claims, N0 Drawings PGF, ANALOGS CROSS REFERENCE TO RELATEDAPPLICATION This application is a continuation-in-part of copendingapplication Ser. No. 112,032, filed Feb. 2, 1971, now U.S. Pat. No.3,775,462, which is a continuationin-part of copending application Ser.No. 30,312, filed Apr. 20, 1970, and now abandoned.

BRIEF DESCRIPTION OF THE INVENTION This invention relates tocompositions of matter, and to methods and intermediates for producingthem. In particular, the several aspects of this invention relates toracemic prostaglandin E (PGE racemic prostaglandin F (PGF and PGF Bracemic prostaglandin A (PGA prostaglandin 8;, (P68 to the correspondingacetylenic prostaglandins, 5,6,17,18-dehydro-PGE 5,6,17,18-dehydro-PGF5,6,17,18- dehydro-PGF 5,6,1 7,l8-dehydro-PGA and 5,6,17,l8-dehydro-PGBto analogs of those prostaglandins and 5,6,17, l8-dehydro-prostaglandins; to processes for producing racemic PGE PGF aPGF B PGA PGB the corresponding 5,6,17,18-dehydroprostaglandins, and theanalogs thereof; to processes for resolving the racemates into the dandlforms; and to chemical intermediates useful in those methods.

Optically active PGE (the natural or d-configuration) is a knownsubstance. Bergstrom, Science 157, 382 1967); Samuelson, J. Amer. Chem.Soc., 85, 1878 (1963). Optically active PGF (a and ,3), obtained by theborohydride reduction of optically active PGE is also a known substance;Samuelson, Biochemica Biophysica Acta, 84, 707 1964); so also isoptically active PGA British Patent Specification No. 1,097,533.Optically active PGE optically active PGF and optically active PGF p arealso disclosed in British Patent specification No. 1,040,544.

The prior art methods for producing prostaglandins are costly anddifficult, the necessary biological materials are limited, and themethods are not adaptable to production of a wide variety ofprostaglandin intermediates and analogs.

It is the purpose of this invention to provide processes for theproduction of compounds with prostaglandin-like activity in substantialamounts and at reasonable cost. The useful compounds produced accordingto the processes of this invention comprise racemic PGE racemic PGFracemic PGF racemic PGA racemic PGB the corresponding 5,6,17,18-dehydro-prostaglandins, and other hitherto unavailable racemic andoptically active analogs thereof such as the enantiomorphs (dand lforms)of PGB and the 5,6,17,18-dehydro compounds.

PGE has the following structure:

FOR, has the following structure;

l0 PGF B has the following structure:

The above formulas represent the natural configuration. Racemic PGE PGFPGF; ,3 PGA and PGB are each represented by the combination of one ofthe above formulas and the mirror image (enantiomorph) ofthat formula.See Nature, 212, 38 (1966) for discussion of the stereochemistry of theprostaglandins. 'In formulas I, II, III, IV, and V, as well as in theformulas given hereinafter, broken line attachments to the cyclopentanering indicate substituents in alpha configuration, i.e., below the planeof the cyclopentane ring. Heavy solid line attachments to thecyclopentane ring indicate substituents in beta configuration, i.e.,above the plane of the cyclopentane ring. PGE For, ,PGF ,PGA and PGB arederivatives of prostanoic acid which has the following structure andatom numbering:

2 cooH A systematic name for prostanoic acid is 7-([(2B- octyl)eyclopentl a-yl heptanoic acid.

Compounds similar to formula VI but with carboxylterminated side chainsattached to the cyclopentane ring in beta configuration are designated8-iso-prostanoic acids, and have the following formula:

Vll

wherein R, is hydrogen, alkyl of one to 8 carbon atoms, inclusive,cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbonatoms, inclusive, phenyl, phenyl substituted with one to 3 chloro oralkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the,B-position with 3 chloro, 2 or 3 bromo, or I, 2, or 3 iodo; wherein Ris alkyl of one to 4 carbon atoms, inclusive, substituted with zero to 3fiuoro; wherein R and R are hydrogen or alkyl of one to 4 carbon atoms,inclusive; wherein n is an integer of one to 4, inclusive; wherein A isalkylene of one to 10 carbon atoms, inclusive, substituted with zero to2 fluoro, and with one to 5 carbon atoms, inclusive, between COOR andand pharmacologically acceptable salts thereof wherein R is hydrogen.

Prostaglandin F and its analogs and isomers produced according to theprocesses of this invention are represented by the formula:

H Xe

wherein R R R R and A are as defined above for formula Vllle, and thepharmacologically acceptable salts thereof wherein R is hydrogen.

Prostaglandin B and its analogs and isomers (including itsenantiomorphs) produced according to the processes of this invention arerepresented by the formula:

wherein R R R R and A are defined above for formula Vllle, andpharmacologically acceptable salts thereof wherein R is hydrogen.

The wave line, as used above, and elsewhere herein, includes bothconfigurations, i.e., alpha and beta, or endo or exo. The word racemicindicates an equal mixture of a compound of the formula shown, whichisthe natural cofiguration, and its enantiomorph.

Compounds of formula VIIIe, IXe, Xe, and Xle have their counterpartwhere the cis-ethylenes are dehydro, i.e., ethynylene. These dehydroanalogs here designated as VIIId, IXd, Xd, and XId, are intermediates,as

formulas VIII, IX, and X have the trans CH=C- R CR OH side chainattached in beta configuratron.

Formulas Vllle, IXe, Xe, and Xle represent PGE PGF PGA and PGBrespectively, when in these formulas R R and R are each hydrogen, n is1, R is ethyl, A is trim'ethylene, the attachment of -CI-I-CI-I=CI-IACOOR, to the cyclopentane ring is in alpha configuration, andthe configuration of the side chain hydroxy is S.

With regard to formulas VIII to XI, inclusive, examples of alkyl of oneto 4.carbon atoms, inclusive, are methyl, ethyl, propyl, butyl, andisomeric forms thereof. Examples of alkyl of one to 8 carbon atoms,inclusive, are those given above, and pentyl, hexyl, heptyl, octyl, andisomeric forms thereof. Examples of alkyl of one to 10 carbon atoms,inclusive, are those given above, and nonyl, decyl, and isomeric formsthereof. Examples of cycloalkyl of 3 to carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are cyclopropyl,Z-methylcyclopropyl, 2,2- dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butylcyclopropyl, cyclobutyl, Z-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2- dimethylcyclopentyl,3-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Examples of aralkylof 7 to 12 carbon atoms, inclusive, are benzyl, phenethyl, l-phenethyl,l-phenylethyl, Z-phenylpropyl, 4-phenylbutyl, 3-phenylbutyl, 2-(l-naphthylethyl), and l,-(2-naphthylmethyl). Examples of phenylsubstituted by one to 3 chloro or alkyl of one to 4 carbon atoms,inclusive, are p-chlorophenyl, mchlorophenyl, o-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethyl phenyl, p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-Z-methylphenyl, and 2,4-dichloro-3-methylphenyl.

Examples of alkylene of one to 10 carbon atoms, inclusive, aremethylene, ethylene, trimethylene, tetramethylene, pentamethylene, andisomeric branched chain forms thereof, 1-, 2-, and3-methylpentamethylene, l, 2-, 3-ethylpentamethylene, 1-, 2- and 3-propylpentamethylene, l-, 2-, and 3-butylpentamethylene, and l-, 2-, and3-pentylpentamethylene.

Examples of alkyl of one to 4 carbon atoms, inclusive, substituted withone to 3 fluoro, are 2-fluoroethyl, 2-fluorobutyl, 3-fluorobutyl,4-fluorobutyl, 3,4- difluorobutyl, 2,2,2-trifluoroethyl, and4,4,4-trifluorobutyl. 1

Examples of alkylene of one to 10 carbon atoms, inclusive, substitutedwith one or 2 fluoro, have the formulas PGE PGF a PGF ,3 PGA and PGB andtheir esters and pharrnacologically acceptable salts, are extremelypotent in causing various biological responses. For that reason, thesecompounds are useful for pharmacological purposes. See, for example,Bergstrom et al., Pharmacol. Rev. 20, l (1968), and references citedtherein. A few of those biological responses are systemic arterial bloodpressure lowering in the case of PGE PGF 3 and PGA as measured, forexample, in anesthetized (pentobarbital sodium) pentoliniumtreated ratswith indwelling aortic and right heart cannulas; pressor activity,similarly measured, for PGE stimulation of smooth muscle as shown, forexample, by tests on strips of guinea pig ileum, rabbit duodenum, orgerbil colon; potentiation of other 7 smooth muscle stimulants;antilipolytic activity as shown by antagonism of epinephrine-inducedmobilization of free fatty acids or inhibition of the spontaneousrelease of glycerol from isolated rat fat pads; inhibition of gastricsecretion in the case of PGE and PGA as shown in dogs with secretionstimulated by food or histamine infusion; activity on the centralnervous system; decrease of blood platelet adhesiveness as shown byplatelet-to-glass adhesiveness, and inhibition of blood plateletaggregation and thrombus formation induced by various physical stimuli,e.g., arterial injury, and various biochemical stimuli, e.g., ADP, ATP,serotonin, thrombin, and'collagen; and in the case of PGE and PBGstimulation of epidermal proliferation and keratinization as shownwhenapplied in culture to embryonic chick and rat skin segments.

Optically active PGE and its esters and pharmacologically acceptablesalts, are also extremely potent in causing the same biologicalresponses as PGE Horton et al., Brit. J. of Pharm. and Chemotherapy, 21,182 (1963); Bergstrom et al., acta physiol. science, 59, 493 (1963);Heinberg et al., .1. Clinic. Investigation, 43, 1533 (1964); Bergstromet al., acta physiol. science,

60, 17 0 1964); and Sandberg et al., A'cta Obstetrica et GynecolojicaScience, 43, 1964). Optically active PGFg and PGA;, which are obtainedfrom optically-active PGE also cause the same biological responses asPGF and PGA Because of these biological responses, these known gestants.For this pur pose, thecompounds are used in a dose range of about 'lOug. to about 10 mg. per ml. of a pharmacologically suitable liquidvehicle or as an aerosol spray, both for topical application. PGE issimilarly useful when administered in equivalent doses PGE and PGA areuseful in mammals, including man and certain useful animals, e.g., dogsand pigs, to reduce and control excessive gastric secretion, therebyreducing or avoiding gastrointestinal'ulcer formation, and acceleratingthe healing of such ulcers already present in the gastrointestinaltract. For this purpose, the compounds are injected or infusedintravenously, subcutaneously, or intramuscularly in an infusion doserange about 0.1 p.g. to about 500 pg; per-kg. of body weight per minute,or in a total daily dose by injection of infusion in the range about 0.1to about 20 mg. per kg. of body weight per day, the exact dose dependingon the age, weight, and condition of the patient or animal, and on thefrequency and route of administration. PGE and PGA are similarly'usefulwhen administered in equivalent doses.

PGE PGA PGF a and PGF p are useful whenever it is desired to inhibitplatelet aggregation, to re-' duce the adhesive character of platelets,and to remove or prevent the formation of thrombi in mammals, includingman, rabbits, and rats. For example, these compounds are useful in thetreatment and prevention of myocardial infarcts, to treat and preventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. For these purposes, these compoundsare administered systemically, e.g., intraveneously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response, especially in emergency situations, theintravenous route of administration is preferred. Doses in the rangeabout 0.004 to about 20 mg. per kg. of body weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration. PGE PGA PGFand FOR, 3 are similarly useful when administered in equivalent doses.

PGE PGA PGF and PGF B are especially useful as additives to blood, bloodproducts, blood substitutes, and other fluids which are used inartificial extracorporeal circulation and perfusion of isolated bodyportions, e.g., limbs and organs, whether attached to the original body,detached and being preserved or pre pared for transplant, or attached toa new body. During these circulations and perfursions, aggregatedplatelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the ciruclating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplatns. PGE PGA PFG andPGF B are similarly useful when administered in equivalent doses.

PGE is extremely potent in causing stimulation of smooth muscle, and isalso highly active in potentiating other known smooth musclestimulators, for example, oxytocic agents, e.g., oxytocin, and thevarious ergot alkaloids including derivatives and analogs thereof.Therefore PGE is useful in place of or in combination with less thanusual amounts of these known smooth muscle stimulators, for example, torelieve the symptoms of paralytic ileus, to control or prevent atonicuterine bleeding after abortion or delivery, to aid in expulsion of theplacenta, and during the puerperium. For these purposes, PGE isadministered by intravenous infusion immediately after abortion ordelivery at a dose in the range about 0.01 to about 50 pg. per kg. ofbody weight per minute until the desired effect is obtained. Subsequentdoses are given by intravenous. subcutaneous, or intramuscular injectionor infusion during puerperium in the range 0.01 to 2 mg. per kg. of bodyweight per day, the exact dose depending on the age, weight, andcondition of the patient or animal. PGE is similarly useful whenadministered in equivalent doses.

PGE PGA and PGF 3 are useful as hypotensive agents to reduce bloodpressure in mammals, including man. For this purpose, the compounds areadministered by intraveneous infusion at the rate about 0.01 to about 50pg. per kg. of body weight per minute or in single or multiple doses ofabout 25 to. 500 pg. per kg. of body weight total per day. PGE PGA andPGF p are similarly useful when administered in equivalent doses.

PGE PGF and PGF B are useful in place of oxytocin to induce labor inpregnant animals, including man, cows. sheep, and pigs, at or near term,or in pregnant animals with intrauterine death of the fetus from aboutweeks to term. For this purpose, the compound is infused intravenouslyat a dose 0.01 to 50 pg. per kg. of body weight per minute until or nearthe termination of the second stage of labor, i.e., expulsion of thefetus. These compounds are especially useful when the female is one ormore weeks post-mature and natural labor has not started, or l2 to 60hours after the membranes have ruptured and natural labor has not yetstarted. PC113 PGF a and PGF B are similarly useful when administered inequivalent doses.

PGF a PGF B and PGE are useful for controlling the reproductive cycle inovulating female mammals, including humans and animals such as monkeys,rats, rabbits, dogs, cattle, and the like. For that purpose, PGF isadministered systemically at a dose level in the range 0.01 mg. to about20 mg. per kg. of body weight of the female mammal, advantageouslyduring a span of time starting approximately at the time of ovulationand ending approximately at the time of menses or just prior to menses.PGE PGF and PGF p are similarly useful when administered in equivalentdoses.

As mentioned above, PGE is a potent antagonist of epinephrine-inducedmobilzation of free fatty acids. For this reason, this compound isuseful in experimental medicine for both in vitro and in vivo studies inmammals, including man, rabbits, and rats, intended to lead to theunderstanding, prevention, symptom alleviation, and cure of diseasesinvolving abnormal lipid mobilization and high free fatty acid levels,e.g., diabetes mellitus, vascular diseases, and hyperthyroidism. PGE issimilarly useful when administered in equivalent doses.

PGE and PGB promote and accelerate the growth of epidermal cells andkeratin in animals, including humans, useful domestic animals, pets,zoological specimens, and laboratory animals. For that reason, thesecompounds are useful to promote and accelerate healing of skin which hasbeen damaged, for example, by burns, wounds, and abrasions, and aftersurgery. These compounds are also useful to promote and accelerateadherence and growth of skin autografts, especially small, deep (Davis)grafts which are intended to cover skinless areas by subsequent outwardgrowth rather than initially, and to retard rejection of homografts. PGEand PGB are similarly useful when administered in equivalent doses.

For these purposes, these compounds as well as the compounds of theinvention are preferably administered topically at or near the sitewhere cell growth and keratin formation is desired, advantageously as anaerosol liquid or micronized powder spray, as an isotonic aqueoussolution in the case of wet dressings, or as a 10- tion, cream, orointment in combination with the usual pharmaceutically acceptablediluents. In some instances, for example, when there is substantialfluid loss as in the case of extensive burns or skin loss due to othercauses, systemic administration is advantageous, for example, byintravenous injection or infusion, separate or in combination with theusual infusions of blood, plasma, or substitutes thereof. Alternativeroutes of administration are subcutaneous or intramuscular near thesite, oral, sublingual, buccal, rectal, or vaginal. The exact dosedepends on such factors as the route of administration, and the age,weight, and condition of the subject. Especially for topical use, theseprostaglandins are useful in combination with antiobiotics, for example,gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of these being used in thecombination at the usual concentration suitable for its use alone.

Racemic PGE racemic PGF racemic PGF B and racemic PGA each are usefulfor the purposes described above for the optically active compounds, butthese racemic compounds offer the enormous advantage of being availablein unlimited quantities at much lower cost. Racemic PGB has likeadvantages and is useful for the same purposes as PGB Moreover, theseracemic compounds are easier to purify since they are produced bychemical reactions rather than by extraction from biological materialsor enzymatic reaction mixtures.

The PGE PGF PGA and PGB analogs and isomers cause correspondingbiological responses and are useful for corresponding purposes as PGEPGF PGA and PGB respectively.

To obtain the optimum combination of biological response specificity andpotency, certain compounds within the scope of formulas Vllle and IXeare preferred. As discussed above, those formulas represent the PGE-type compounds and the PGF -type compounds. respectively. Referring toformulas Vllle and lXe, when Cl-l -CH=CH-ACOOR is attached in alphaconfiguration and, in the case of formula IXe, when the ring hydroxy isalso attached in alpha configuration, the sterochemistry is typical ofthe known optically active PGE and PGF a According to this invention,preferred formula Vllle and IXe compounds are those wherein Cl-l-Cl-l=CH-ACOOR, and ring hydroxy are alpha, n is l and A istrimethylene, R is hydrogen and R is hydrogen or methyl and R is ethyl.These preferred compounds exhibit superior biological responsespecificity and/or potency.

Certain compounds within the scope of formulas Ville to Xle areespecially useful for one or more of the purposes stated above, becausethey have a substantially longer duration of activity than othercompounds within the generic formulas, including PGE PGF a PGF B PGA andP68 and because they can be administered orally, sublingually,intravaginally, buccally, or rectally, rather than by the usualintravenous, intramuscular, or subcutaneous injection or infusion asindicated above for the uses of these known prostaglandins and the othercompounds encompassed by formulas Vllle to Xle. These qualities areadvantageous because they facilitate maintaining uniform levels of thesecompounds in the body with fewer, shorter, or smaller doses, and makepossible self-administration by the patient.

With reference to formulas Vllle to Xle, these special compounds includethose wherein A is -(Cl-l Z-, wherein b is zero, one, 2, or 3, and Z isethylene substituted by one or 2 fluoro, methyl, or ethyl, or by onealkyl of 3 or 4 carbon atoms. These special compounds also include thosewherein R is ethyl, propyl, isopropyl, isobutyl, tert-butyl,3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl. Thesespecial compounds also include those wherein A is (CH ),,Z- as abovedefined, and R is ethyl, propyl, isopropyl, isobutyl, tert-butyl,3,3-difluorobutyl, 4,4- difluorobutyl, or 4,4,4-trifluorobutyl.Especially preferred among these special compounds are those wherein Rand R are both hydrogen.

In the case of Z, the divalent ethylene group, CH- Cl-l is substitutedon either or both carbon 10 atoms, i.e., alpha and/or beta to thecarboxylate function. For example, Z is CH CHF, CH-

F-CH CH -CF CHF-CHF, -CH- -CH(CH CH(CH )CH CH -C(CH )2, 3)2 2, 3) Q) andsimilarly for ethyl, and for one fluoro and one methyl, one fluoro andone ethyl, and one methyl and one ethyl. Z is alternatively ethylenesubstituted on either carbon atom with propyl, isopropyl, butyl,isobutyl, sec-butyl, or tert-butyl.

Although all of the special compounds just described have the specialadvantages of long duration and oral, sublingual intravaginal, andrectal routes of administration, there is a still more limited group ofcompounds encompassed by these formulas which have these qualities in aparticularly high degree. Those are the compounds wherein A is CH -Z,i.e., wherein b in -(CH ,Z is one, especially when Z is ethylene withone fluoro or methyl, with 2 fluoro or 2 methyl on the same carbonatoms, or with butyl, isobutyl, secbutyl, or tert-butyl on the carbonatoms alpha (adjacent) to the carboxylate function, the compoundswherein R2 is 'C(CH3)3, CH2CH(CH3)2, CH2CF3, Cl-l CHF or CH CF CH andthe compounds wherein both A and R are both defined in these morelimited ways. I

Racemic PGE racemic PGF racemic PGF p racemic PGA racemic P68 and theother compounds encompassed by formulas VIlle and Xle, are used for thepurposes described above in the free acid form, in ester form, or inpharmacologically acceptable salt form. When the ester form is used, theester is any of those within the above definition of R However, it ispreferred that the ester be alkyl of one to four carbon atoms,inclusive. Of those alkyl, methyl and ethyl are especially preferred foroptimum absorption of the compound by the body or experimental animalsystem.

Pharmacologically acceptable salts of these formula VIIIe, IXe, Xe, andXle compounds useful for the purposes described above are those withpharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron, are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, B-phenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 carbonatoms, as well as heterocyclic amines, e.g., piperidine, morpholine,pyrrolidine, piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine 4-ethylmorpholine, l-isopropylpyrrolidine,2-methylpyrrolidine, 1,4- dimethylpiperazine, 2-methylpiperidine, andthe like, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2-aminol-butanol, 2-amino-2-ethyll ,3-propanediol,2-amino- 11 2-methyl-1-propanol, tris( hydroxymethyl)aminomethane,N-phenylethanolamine, N-(p-tert-amylphenyl)- diethanolamine,galactamine, N-methylglucamine, N- methylglucosamine, ephedrine,phenylephrine, epimephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternary ammoniumcations are tetramethylammonium, tetraethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of formulas Vllle to XIe areadministered in various ways for various purposes; e.g., intravenously,intramuscularly, subcutaneously, orally, intravaginally, rectally,buccally, sublingually, topically, and in the form of sterile implantsfor prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For the purpose, it is preferred because ofincreased water solubility that R, in the formula VlIIe to Xle compoundbe hydrogen or a pharmacologically acceptable cation. For subcutaneousor intramuscular injection, sterile solutions or suspensions of theacid, salt, or ester form in aqueous or non-aqueous media are used.Tablets, capsules, and liquid preparations such as syrups, elixers, andsimple solutions, with the usual pharmaceutical carriers are used fororal or sublingual administration. For rectal or vaginal administration,suppositories prepared as known in the art are used. For tissueimplants, a sterile table or silicone rubber capsule or other objectcontaining or impregnated with the substance is used.

Racemic PGE racemic PGF a racemic PGF racemic PGA racemic PGB and theother compounds encompassed by formulas VIIIe, IXe, Xe, and Xle areproduced by the reactions and procedures described hereinafter. Asintermediates there are produced the corresponding5,6,17,18-dehydroprostaglandins VIIId, IXd, Xd, and XId which in thefree acid or salt forms are useful also for the purposes given above.

The enantiomorphs of the VIII, IX, X, and XI compounds are formed eitherby resolution of the final product racemate or a racemic intermediate.

These ring carbonyl reductions are carried out by methods known in theart for ring carbonyl reductions of known prostanoic acid derivatives.See, for example, Bergstrom et al., Arkiv Kemi, 19, 563 (1963), and ActaChem. Scand. 16, 969 1962), and British patent specification No.1,097,533. Any reducing agent is used which does not react withcarbon-carbon double bonds or ester groups. Preferred reagents arelithium (tri-tertbutoxy) aluminum hydride and the metal borohydrides,especially sodium, potassium and zinc borohydrides. The mixtures ofalpha and beta hydroxy reduction products are separated into theindividual alpha and beta isomers by methods known in the art for theseparation of analogous pairs of known isomeric prostanoic acidderivatives. See, for example, Bergstrom et al., cited above, Granstromet al., J. Biol. Chem. 240, 457 (1965), and Green et al., J. LipidResearch, 5, 117 (1964). Especially preferred as separation methods arepartition chromatographic procedures, both normal and reversed phase,preparative thin layer chromatography, and countercurrent distributionprocedures. They can be applied either before or after the hydrogenationof the acetylenic bonds.

Racemic PGA and the other PGA -type compounds encompassed by formula Xare prepared by acidic dehydration of the corresponding PGE -typecompounds encompassed by formula VIII. For example, acidic dehydrationof racemic PGE VIIIe, gives racemic PGA Xe. The corresponding5,6,17,18-dehydro-PGA -type compounds Xd, are produced in a like mannerfrom 5,6,l7,18-dehydro-PGE -type compounds, Vllld, and by hydrogenationof the acetylenic bonds are converted to PGA -type compounds, Xe.

These acidic dehydrations are carried out by methods known in the artfor acidic dehydrations of known prostanoic acid derivatives. See, forexample, Pike et al., Proc. Nobel Symposium II, Stockholm (1966),Interscience Publishers, New York, p. 161 (1967); and British patentspecification No. 1,097,533. Alkanoic acids of 2 to 6 carbon atoms,inclusive, especially acetic acid, are preferred acids for this acidicdehydration. They can be applied either before or after thehydrogenation of the acetylenic bonds.

Racemic PGB and the other compounds encompassed by formula XIe areprepared by basic dehydration of the corresponding PGE -type compoundsencompassed by formula Vllle or by contacting the corresponding PGA-type compounds encompassed by formula Xe with base. For example, bothracemic PGE VIIIe, and racemic PGA Xe, give racemic PGB Xle, ontreatment with base. Presumably the base first causes dehydration of thePGE to PGA and then causes the ring double bond of PGA to migrate to anew position. The corresponding 5,6,17,18-dehydro- PGB -type compounds,XId, are produced in a like manner from 5,6,17,18-dehydro-PGE VIIId, or5,6,17,18-dehydro-PGA -type compounds, Xd, and by hydrogenation of theacetylenic bonds are converted to PGB -type compounds, Xld.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand sufficient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE -type or PGA-type compound is maintained in such a reaction medium until no furtherPGB -type compound is formed, as shown by the characteristic ultravioletlight absorption for the PGB -type compound. They can be applied eitherbefore or after the hydrogenation of the acetylenic bonds.

These various transformations of the PGE -type compounds of formulasVllle to the PGF -type, IXe, PGA type, Xe, and PGB -type, Xle, compoundsare shown in Chart A, wherein R R R R A, and are as defined above. Thesame transformation can be applied to the 5,6,17,18-dehydro-PGE -typecompounds, VIIId, as shown in Chart A-l. If desired, the 5,6,17,18-dehydro- PGA -type compounds, Xd, can be converted to PGA typecompounds. Xe, by hydrogenation by the procedures of step 8 and 8a,infra.

CHART A H\C C/H cuz A-cook R c Hz R2 Xle The bicyclic compound offormula XII in Chart B is the initial reactant in these multi-stepprocesses. It exists in two isomeric forms, exo and endo with respect tothe attachment of the CR O moiety. It also exists in two isomeric formswith respect to the attachment of the tetrahydropyranyloxy group makingin all four isomeric forms. Each of those isomers separately or mixturesthereof are used as reactants according to this invention to producesubstantially the same final PGE type or 5,6,l7,1 8-dehydro-PGE -typeproduct mixture.

In Belgian Pat. No. 702,477; reprinted in Farmdoc CompleteSpecifications, Book 714, No. 30,905, page The exo-endo mixture istreated with a base to isomerize the endo isomer in the mixture to moreof the exo isomer. Next, the carboxylate ester group at 6 is transformedto an aldehyde group or ketone group,

wherein R is as defined above.

In the first step of the process (Chart B), the aldehyde group or ketogroup is transformed by the Wittig reaction to a moiety of the formulaCR =CR CnI-I- n-C a C-R which is in exo configuration relative to thebicyclo ring structure, and is the same as shown in formula XIII. Instep 2, the protective group is removed to regenerate the 3-hydroxy(XIV) which is then oxidized in step 3, for example, by the Jonesreagent, to give the exo compound XV.

Separation of the cis-exo and trans-exo isomers of XV can be effected bythe procedures described in said Belgian patent. However, as mentionedabove, that separation is usually not necessary since the cis-transmixture is useful as a reactant in the next process step.

The process described in said Belgian Pat. No. 702,477 for producing theexo form of bicyclic compound XII uses as an intermediate, the exo formof a bicyclo[3. l .0]-hexane substituted at 3 with a protected hydroxy,e.g., tetrahydropyranyloxy and at 6 with an esterified carboxyl. Whenthe corresponding endo compound is substituted for that exointermediate, the Belgian patent process leads to the endo form ofbicyclic compound XII. That endo intermediate used in the Belgian patentprocess has the formula:

Compound XXVII is prepared by reacting endo-bicy-Clo-[3.1.0lhexl2-ene-6-carboxylic acid methyl ester with diborane in amixture of tetrahydrofuran and diethyl ether, a reaction generally knownin the art, to give endobicyclo[ 3. l .0]hexan-3-ol-6-carboxylic acidmethyl ester which is then reacted with dihydropyran in the presence ofa catalytic amount of POCl to give the desired compound. This is thenused as described in said Belgian patent to produce the endo form ofbicyclic compound XII. Using this endo form of bicyclic compound XII asthe starting material, steps 2 and 3 produce mixtures of endocis andendo-trans. These can be separated as def scribed for the separation ofexo-cis and exo-trans XV, I but this separation is usually not necessarysince, as mentioned above, the cis-trans mixture is useful as a re- 1actant in the next process step.

' In the Wittig reaction, (Step 1), the other starting compound is anorganic chloride or bromide, or iodide I of the formula This can beprepared from the corresponding alcohol I by processes already known inthe art, for example, by

reacting compound XXIX with triphenylphosphine and I Nbromo-succinimide.

I Acetylenic alcohols of formula XXIX are generally known in the art,for example, 3-pentyn-1-ol, 3-hexynl-ol, 4-hexyn-l-ol,2-methyl-3-pentyn-1-ol, 2,3- dimethyl-4-pentyn-l-ol, 6-octyn-l-ol,6-nonyn-l-ol, 4-

undecyn-l-ol, 6-dodecyn-1-ol, S-tetradecyn-l-ol, and g the like. Otherswhere R is methyl, ethyl, propyl, butyl,

or the isomers thereof can be made by reacting an acetylenic aldehyde ofthe formula O=CHC,,l-l ,,--C C-R2 1 XXX with the appropriate Grignardreagent, BrMgR These acetylenic aldehydes can be made by oxidizing thecorresponding alcohol, for example, those listed above, with a Jonesreagent, Collins reagent, a Moffatt oxidation or the like. The aldehydeis then reacted with BrMgR to prepare acetylenic alcohols of formulaXXIX. Compounds thus obtainable include 4-hexyn-2- 23 01, 4-heptyn-2-ol,5-heptyn-2-ol, 3-methyl-4-hexyn-2- ol, 3,4-dimethyl- 5-hexyn-2-ol,7-nonyn-2-ol, 7-decyn- 2-ol, 5-dodecyn-2-ol, 7-tridecyn-2-ol,5-heptyn-3-ol, 5-octyn-3ol, 6-octyn-3-ol, 8-undecyn-3-ol, 6-tridecyn-3-0], 8-tetradecyn-3-ol, and the like. Still other alkyn-l- 015according to formula XXIX (R hydrogen) can be made by condensing anomega-alkyl-l-ol of the formula HOCH,C,,H,,, C 2 CH xxx! with an alkylhalide, HalR using lithium and ammonia as the condensing agent; stillothers by condensing a protected halohydrin of the formula O-CH CnHn-Hal XXXll with a l-alkyn, HC 5 CR Again lithium and ammonia can beused as the condensing agent.

The protective tetrahydropyranyl group known in the-art. See, forexample, Gunstone, Ad-' vances in Organic Chemistry, Vol. 1, pp.103-147, Interscience Publishers, New York, N. Y. (1960). Variousisomeric glycols are obtained depending on whether olefin XXIII is cisor trans and endo or exo, and on whether a cis or a trans hydroxylationreagent is used. Thus endo-cis olefin XXIII gives a mixture of twoisomeric erythro glycols of formula XXIV with a cis hydroxylation agent,e.g., potassium permanganate. The endo-cis olefins and the endo-transolefins XXIII give similar mixtures of two threo isomers with cis andtrans hydroxylation reagents, respectively. These various glycolmixtures are separated into individual isomers by silica gelchromatography. However, this separation is usually not necessary, sinceeach isomeric erythro glycol and each isomeric threo glycol is useful asan intermediate according to this invention and the processes outlinedin Charts B, C, and D to produce final products of formulas VIIIe andXe, and then, according to Chart A, to produce the other final productsof this invention. Thus the various isomeric glycol mixtures encompassedby formula XXIV produced from the various isomeric olefins encompassedby formula XXIII are all useful for these same purposes.

In step 4 the other starting material is a haloalkynoic ester of theformula wherein Hal is chlorine, bromine, or iodine. In effecting I thisstep any of the alkylation procedures known in the art to be useful foralkylating cyclic ketones with alkyl halides, especially haloalkynoicesters, can be used for the transformation of XV to XXIII. See, forexample, the above mentioned Belgian Pat. No. 702,477 for pro ceduresuseful here and used there to carry out similar alkylations.

For this alkylation, it is preferred that Hal be bromo,

or iodo. Any of the usual alkylation bases, e.g., alkali metalalkoxides, alkali metal amides, and alkali metal hydrides, are usefulfor this alkylation. Alkali metal alkoxides are preferred, especiallytert-alkoxides. Sodium and potassium are preferred alkali metals.Especially preferred is potassium tert-butoxide. Preferred diluents forthis alkylation are tetrahydrofuran and 1,2- dimethoxyethane. Otherwise,procedures for producing and isolating the desired formula XXIIIcompound are within the skill of the art.

This alkylation procedure produces a mixture of alpha and betaalkylation products, i.e., a mixture of formula XXIII products whereinpart has the CH C E CACOOR, moiety attached in alpha configuration andwherein part has that moiety attached in beta configuration. When aboutone equivalent of base per equivalent of formula XV ketone is used, thealpha configuration usually predominates. Use of an excess of base andlonger reaction times usually result in production of larger amounts ofbeta products. These alpha beta isomer mixtures are separated at thisstage or at any subsequent stage in the multi-step processes shown inCharts B and D. Silica gel chromatography is preferred for thisseparation.

An alternative alkylation procedure is shown in steps 4a, 4b, and 4c.The alkylating agent XVII is reacted with the bicyclo-ketone-olefin XVby the alkylation procedure described above'for step 4.

The alkylating agent of formula XVII is prepared by the series ofreactions shown in Chart C. The initial reactants, BrACH OH, are omegabromoalcohols which are known in the art or can be prepared by methodsknown in the art. For example, when A in the final product is to betrimethylene as it is in racemic PGE the necessary 4-bromobutanol isprepared by reacting tetrahydrofuran with hydrogen bromide.

To illustrate the availability of the other bromoglycols of formula XXI(Chart C), consider the abovedescribed special compounds of formulaVIIIe, wherein A is -(CH ,,Z, wherein b is Zero, one, 2, or 3, and Z isethylene substituted by one or 2-fluoro, methyl, or ethyl, or by onealkyl of 3 or 4 carbon atoms. These omega-bromoalcohols, Br(CH -Z-CH-0H, are prepared by starting with the appropriate succinic acid,HOOC--ZCOOH, all of which are known or easily accessible by knownmethods. These succinic acids are transformed to the correspondinganhydrides by known procedures. Each anhydride is then reacted with analkanol, for example, methanol, to give the corresponding succinic acidhalf ester, e.g., HOOC-Z- COOCH When Z is unsymmetrical, e.g.,substituted with one fiuoro, a mixture of isomeric half esters isobtained, HOOCZCOOCH and CH -OOCZ- COOI-I, which is separated to givethe desired isomer.

When it is desired that b is Br(CH bZ-CH OI-I be zero, the succinic acidhalf ester is subjected to the Hunsdiecker reaction, thereby producingBr-Z-- COOCl-I which is reduced by lithium aluminum hydride to BrZCI-IOH. When b is to be one, the carboxyl group of the succinic acid halfester is changed to acid chloride with thionyl chloride, to aldehyde bythe Rosenmund reduction, to alcohol with sodium, borohydride, and to CHBr with PBr giving BR-CH- -ZCOQCl-I which is then reduced to Br-CH- Z-CHOH with lithium aluminum hydride. When b is to be 2 or 3, the succinicacid half ester is subjected once or twice to the Arndt-Eistert reactionto produce l-IOOCCH -ZCOOCI-I or I-IOCC-CI-I C- H -ZCOOCH which is thensubjected to the same series of reactions given above to give Br- CH C-Referring again to Chart C, the several process steps, XXI to XX, XX toXIX, XIX to XVIII, and XVIII to XVII are exemplified in Belgian Pat. No.747,348, Sept. 14, 1970, in the case wherein A is trimethylene. Thoseprocedures are used when A is other than trimethylene and within thescope of A as defined above.

The transformation of alkylation product XVI to primary alcohol XXII(Chart B) is carried out by acid catalyzed hydrolysis of thetetrahydropyranyl ether XVI. Such hydrolysis of tetrahydropyranyl ethersis well known to those skilled in the art. Oxalic acidis especiallypreferred for this acid hydrolysis of XVI to XXII.

The oxidation of primary alcohol XXII to carboxylic acid XXIII (Chart E,R H) is carried out by oxidizing XXII with any oxidizing agent whichwill not also attack the acetylenic linkage in XXII. An especiallyuseful reagent for this purpose is the Jones reagent, i.e.,

acidic chromic acid. See J. Chem. Soc. 39 (1946). Acetone is a suitablediluent for this purpose, and a slight excess of oxidant andtemperatures at least as low as about C., preferably about to about C.should be used. The oxidation proceeds rapidly and is usually completein about 5 to about 30 minutes. Excess oxidant is destroyed, forexample, by addition of a lower alkanol, advantageously isopropylalcohol, and the aldehyde is isolated by conventional methods, forexample, by extraction with a suitable solvent, e.g., diethyl ether.Other oxidizing agents can also be used. Examples are mixtures ofchromium trioxide and pyridine or mixtures of dicyclohexylcarbodiimideand dimethyl sulfoxide. See, for example, J. Am. Chem. Soc. 87, 5661(1965).

The acid thus formed (compound XXIII, R H) can then be esterified byprocedures already known in the art for transforming carboxylic acids toesters. For example, a diazohydrocarbon, e.g., diazomethane,advantageously in diethyl ether solution, is reacted with the acid toproduce the ester, e.g., the methyl ester, by known procedures. When R,is ethyl substituted with 3-chloro, 2 or 3 bromo, or I, 2, or 3 iodo,the acid is reacted with the appropriate haloethanol, e.g., B, B,B-trichloroethanol, in the presence of a carbodiimide, e.g.,dicyclohexylcarbodiimide, and a base, e.g., pyridine. This mixture,advantageously with an inert diluent, e.g., dichloromethane, usuallyproduces the desired haloethyl ester within several hours at about C.The other esters within the scope of R are prepared by procedures knownto the art.

In step 6 the vicinal hydroxy groups of the glycol XXIV are modified byreplacing the hydrogens with an alkanesulfonyl leaving-group, L, forexample mesyl, containing up to and including 5 carbon atoms. Thus, thebis-alkanesulfonic acid esters XXV (Chart B) are prepared by reactingglycol XXIV with an alkylsulfonyl chloride or bromide, or with analkanesulfonic acid anhydride. Alkylsulfonyl chlorides are preferred forthis reaction. The reaction is carried out in the presence of a base toneutralize the by-product acid. Especially 5 bis-alkanesulfonic acidesters are then isolated by procedures known to the art.

The transformation in Chart D, Step 7a, of the modified glycol XXV toVIIId is carried out by reacting XXV with water in the range about 0 toabout 60 C. The resulting product is racemic 5,6,17,18-dehydro- PGE oran analog thereof. In making racemic 5,6,l7,l8-dehydro-PGE usually 25 C.is a suitable reaction temperature, the reaction then proceeding tocompletion in about 5 to 10 hours. It is advantageous to have ahomogenous reaction mixture. This is accomplished by adding sufficientof a water-soluble organic diluent which does not enter into thereaction. Acetone is a suitable diluent. The desired product is isolatedby evaporation of excess water and diluent if one is used. The residuecontains a mixture of formula VIIId isomers which differ in theconfiguration of the side chain hydroxy, that being either R or S. Theseare separated from by-products and from each other by silica gelchromatography. A usual by-product is the mono-sulfonic acid ester offormula XXVI (Chart D). This mono-sulfonic acid ester is esteritied tothe formula XXV bis-sulfonic acid ester in the same manner describedabove for the transformation of glycol XXIV to bis-ester XXV, and thusis recycled in step 7a. For the transformation of bis-esters XXV to theformula VIIId products, it is preferred to use the bis-mesyl esters,i.e., compounds XXV wherein L is mesyl.

In step 82 the acetylenic linkages are hydrogenated to olefiniclinkages. A suitable method is to hydrogenate over a Lindlar catalyst inthe presence of quinoline. The Lindlar catalyst is 5%palladium-on-barium sulfate. Methanol or like inert solvent or diluentis used and the pressure is low, advantageously slightly aboveatmospheric and ordinarily not above about two atmospheres. Theresulting products can be isolated by silica gel chromatography. If thestarting material contains both the R and S epimers, the product VIIIewill also contain the R and S epimers. These also can be separated bysilica gel chromatography. As shown on Chart D, the hydrogenation ofVIIId (or Xd) leads to PG,- type compounds depending on whether theacetylenic bonds of VIIId (or Xd) are reduced to cis-CH=CH. The abovedescribed hydrogenation gives this type of reduction of the acetylenicbonds.

The transformation of the protected glycols XXV (Step 7b) to 5,6,l7,l8-dehydro-PGA -type compounds (Xd) is carried out by heating the formulaXXV bisester in the range to 100 C. with a combination of water, a basecharacterized by its water solution having a pH 8 to 12, and sufficientinert water-soluble organic diluent to form a basic and substantiallyhomogenous reaction mixture. A reaction time of one to 10 hours isusually used. Preferred bases are the water-soluble salts of carbonicacid, especially alkali metal bicarbonates, e.g., sodium bicarbonate. Asuitable diluent is acetone. The products are isolated and separated asdescribed above for step 7a and hydrogenated as in step 8a. The samemono-sulfonic acid esters XXVI observed as byproducts in step 7a arealso observed in step 7b. Also, as in step 7b the bis-mesyl esters XXVare preferred. Also as in steps 7a and 8a, during production of Xd andXe, alpha XXV gives alpha Xd and alpha Xe, beta XXV gives beta Xd andbeta Xe, and in each case,

alpha and beta Xd and Xe, a mixture of R and S isomers is obtained.These R and S isomer mixtures are separated by silica gelchromatography. The configuration of the CACOOR moiety does not changeduring these transformations of Charts B and D. Also the configurationdoes not change in hydrogenation. Therefore, when the CI-I C E C-A-COORis attached initially in alpha configuration racemic5,6,17,18-dehydro-PGE -type, VIIId, PGE -type, VIIIe, 5,6,17,18-dehydro-PGA -type, Xd, and PGA -type, Xe, compounds are obtained, andwhen the moiety is attached in beta configuration, the 8-isoforms areobtained.

Resolution of the final product racemates or the racemic intermediatesare carried out by procedures known in the art. For example, when afinal compound of formula VIIIe, IXe, Xe, or XIe is a free acid, the dlform (racemate) thereof is resolved into the d and 1 forms (the naturaland unnatural configurations) by reacting said free acid by knowngeneral procedures with an optically active base, e.g., brucine orstrychnine, to give a mixture of two diastereoisomers which areseparated by known general procedures, e.g., fractional crystallization,to give the separate diastereoisomeric salts. The optically active acidof formula VIII to XI is then obtained by treatment of the salt with anacid by known general procedures. Alternatively, the free acid form ofthe intermediate dehydro compounds VIIId, IXd, Xd, or XId is resolvedinto separate (1 and 1 forms and then esterified and transformed furtherto the corresponding optically active form of the final product VIIIe toXIe as described above.

Alternatively, glycol reactant XXIV, in exo or endo form, is transformedto a ketal with an optically active l ,2-glycol, e.g.,D()-2,3-butanediol, by reaction of said 1,2-glycol with the formula XXIVcompound in the presence of a strong acid, e.g., p-toluenesulfonic acid.The resulting ketal is a mixture of diastereoisomers which is separatedinto the d and l diastereoisomers, each of which is then hydrolyzed withan acid, e.g., oxalic acid, to the original keto compound, now inoptically active form. These reactions involving optically activeglycols for resolution purposes are generally known in the art. See, forexample, Chem. Ind. 1664 (1961) and J. Am. Chem. Soc. 84, 2938 (1962).Dithiols may be used instead of glycols.

The novel PGE PGF PGA and PGB -type compounds of formula VIIIe to XIewherein R is alkyl of one to 4 carbon atoms, inclusive, preferablymethyl or ethyl, are preferred over the corresponding PGE PGF PGA andPGB -type compounds in which R is hydrogen for the above-describedpharmacological purposes. For convenience the compounds of the inventionwhere R is alkyl will be referred to as IS-alkyl analogs even though thenumber actually will be greater or less than depending on whether thenumber of methylene groups in A is greater or less than three.

These 15-alkyl prostaglandin analogs are surprisingly and unexpectedlymore useful than the corresponding IS-hydrogen compounds for the reasonthat they are substantially more specific with regard to potency incausing prostaglandin-like biological responses, and have asubstantially longer duration of biological activity. For that reason,fewer and smaller doses of these 15-alkyl prostaglandin analogs areneeded to attain the desired pharmacological results.

Although the above-mentioned l5-alkyl compounds are produced by themethods outlined above in Charts A-D, the preferred methods are setforth in Charts E and F as follows.

CHART E CH -Q-ACOOR;

(Oxidation) CH -Q-ACOOR In Chart E is shown the transformation ofl-alkyl PGF-type acids and alkyl esters to the corresponding S PGE-typeacids and alkyl esters by oxidation. For this purpose, an oxidizingagent is used which selectively oxidizes secondary hydroxy groups tocarbonyl groups in the presence of carbon-carbon double bonds. FormulalXa in Chart E includes optically active compounds as shown and racemiccompounds of that formula and the mirror images thereof, and also theepimers of both of those, i.e., wherein the configuration at C-l5is Rrather than S as shown. Also in Chart E, A, R,, R and R are as definedabove, R is alkyl of one to 4 carbon atoms, and both Qs are ethynyleneor cisethylene.

For the transformations of Chart E, the B-hydroxy isomers of reactantIXa are suitable starting materials when the carboxyl side chain isalpha, although the corresponding a-hydroxy isomers are also useful forthis purpose.

Oxidation reagents useful for the transformation set forth in Chart Eare known to the art. An especially useful reagent for this purpose isthe Jones reagent, i.'e., acidified chromic acid. See J. Chem. Soc. 39(1946). Acetone is a suitable diluent for this purpose, and a slightexcess beyond the amount necessary to oxidize one of the secondaryhydroxy groups of the formula IXa reactant is used. Reactiontemperatures at least as low as about 0 C. should be used. Preferredreaction temperatures are in the range to 50 C. The oxidation proceedsrapidly and is usually complete in about 5 to 20 minutes. The excessoxidant is destroyed, for example by addition of a lower alkanol,advantageously, isopropyl alcohol, and the formula VIIla PGE- typeproduct is isolated by conventional methods.

Examples of other oxidation reagents useful for the Chart Etransformations are silver carbonate on diatomite [Chem Commun. 1102(1969)], mixtures of chromium trioxide and pyridine [Tetrahedron Letters3363 (1968, J. Am. Chem. Soc. 75, 422 (1953), and Tetrahedron, 18, 1351(1962)], mixtures of sulfur trioxide in pyridine and dimethyl sulfoxide[J Am. Chem. Soc. 89, 5505 (1967)], and mixtures ofdicyclohexylcarbodiimide and dimethyl sulfoxide [J. Am. Chem. Soc. 87,5661 (1965)].

The novel lS-alkyl PGF and PGF 5 -type acids and esters of formula IXaare preferably prepared from the corresponding l5-hydrogen compounds bythe sequence of transformations shown in Chart F, wherein formulas Ix,XXXVII, XXXVIII, IXa(S), and IXa(R) include optically active compoundsas shown and racemic compounds of those formulas and the mirror imagesthereof. Also in Chart F, R is alkyl of one to 4 carbon atoms,inclusive, and A, R R R are as heretofore defined and Q is ethynylene orcis-ethylene. Also in Chart F, G is alkyl of one to 4 carbon atoms,inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenylsubstituted with one or 2 fluoro, chloro, or alkyl of one to 4 carbonatoms, inclusive, and R is alkyl or silyl of the formula Si(G) wherein Gis as defined above. The various GS of a Si(G) moiety are alike ordifferent. For example, a Si(G) can be trimethylsilyl,dimethylphenylsilyl, or methylphenylbenzylsilyl. Examples of alkyl ofone to 4 carbon atoms, inclusive, are methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, and tert-butyl. Examples of aralkyl of 7 to12 carbon atoms, inclusive, are benzyl, phenethyl, a-phenylethyl,3-phenylpropyl, a-naphthylmethyl, and Z-(B-naphthyDethyl. Examples ofphenyl substituted with one or 2 fluoro, chloro, or alkyl of one to 4carbon atoms, inclusive, are p-chlorophenyl, mfluorophenyl, o-tolyl,2,4-dichlorophenyl, p-tert-butylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3- methylphenyl.

In Chart F, the final PGF a and PGF 3 -type products are thoseencompassed by formulas IXa(S) and IXa(R), respectively, where both Qsare cis-ethylene.

The heretoforerdescribed acids and esters of formula IX are transformedto the corresponding intermediate l5oxo acids and esters of formulaXXXVII, by oxidation with reagents such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, activated manganese dioxide, or nickel peroxide (seeFieser et al., Reagents for Organic Synthesis, John Wiley & Sons, Inc.,New York, N.Y., pp. 215, 637, and 731). Alternatively, these oxidationsare carried out by oxygenation in the presence of theIS-hydroxyprostaglandin dehydrogenase of swine lung [see Arkiv for Kemi25, 293 1966)]. These reagents are used according to procedures known inthe art. See, for example, J. Biol. Chem. 239, 4097 (1964).

The novel 5,6,l7,l8-dehydro-PGF5-type compounds of formula IXa areobtained by the borohydride reduction of the corresponding5,6,l7,l8-dehydro-PGE type compounds of formula VIIIa. Here again thenumbering is merely typical and will vary according to the values of Aand n.

Referring again to Chart F, the intermediate compounds of formula XXXVIIare transformed to silyl derivatives of formula XXXVIII by proceduresknown in the art. See, for example, Pierce, Silylation of OrganicCompounds, Pierce Chemical Co., Rockford, Ill. (1968). Both hydroxygroups of the formula XXXVII reactants are thereby transformed to--OSi--(G) moieties wherein G is as defined above, and sufficient of thesilylating agent is used for that purpose according to known procedures.When R is the formula XXXVII intermediate is hydrogen, the COOH moietythereby defined is simultaneously transformed to COOSi(G) additionalsilylating agent being used for this purpose. This latter transformationis aided by excess silylating agent and prolonged treatment. When R informula XXXVII is alkyl, then R in formula XXXVIII will also be alkyl.The necessary silylating agents for these transformations are known inthe 7 art or are prepared by methods known in the art. See, for example,Post, Silicones and Other Organic Silicon Compounds, Reinhold PublishingCorp., New York, N.Y. (1949).

Referring again to Chart F the intermediate silyl compounds of theformula XXXVIII are transformed to the final compounds of formulasIXa(S) and IXa(R) by first reacting the silyl compound with a Grignardreagent of the formula R MgHal wherein R is as defined above, and Hal ischloro, bromo, or iodo. For this purpose, it is preferred that Hal bebromo. This reaction is carried out by the usual procedure for Grignardreactions, using diethyl ether as a reaction solvent and saturatedaqueous ammonium chloride solution to hydrolyze the Grignard complex.The resulting disilyl or trisilyl tertiary alcohol is then hydrolyzedwith water to remove the silyl groups. For this purpose, it isadvantageous to use a mixture of water and sufficient of awater-miscible solvent, e.g., ethanol to give a homogenous reactionmixture. The hydrolysis is usually complete in 2 to 6 hours at 25 C.,and is preferably carried out in an atmosphere of an inert gas, e.g.,nitrogen or argon.

The mixture of 15-8 and l5-R isomers obtained by this Grignard reactionand hydrolysis is separated by procedures known in the art forseparating mixtures of prostanoic acid derivatives, for example, bychromatography on neutral silica gel. In some instances, the lower alkylesters, especially the methyl esters of a pair of 15-5 and lS-R isomersare more readily separated by silica gel chromatography than are thecorresponding acids. In those cases, it is advantageous to esterify themixture of acids, separate the two esters, and then, if desired,saponify the esters by procedures known in the art and described herein.

The novel l5-alkyl PGA-type acids and esters of formula Xa are preparedfrom the l5-alkyl PGE compounds, Vllla, heretofore described, bydehydration as shown in Chart G. For this purpose, a dehydrating agentis used which removes the hydroxy group from the alicyclic ring in thepresence of a hydroxy group on a tertiary carbon atoms. Formula Vlllaincludes optically active compounds as shown and racemic compounds ofthat formula and the mirror images thereof, and also the 15-epimers ofboth of those, i.e., wherein the configuration at C-l 5 is R or S andthat of the carboxyl side chain is a or ,8.

Dehydration agents useful for the transformation to PGA -type compoundsset forth in Chart G are known in the art. Any of the knownsubstantially neutral dehydrating agents is used for these reactions.See Fieser et al., Reagents for Organic Syntheses, John Wiley & Sons,Inc., New York, 1967. Preferred dehydrating agents are mixtures of atleast an equivalent amount of a carbodiimide and a catalytic amount of acopper (II) salt. Especially preferred are mixtures of at least anequivalent amount of dicyclohexylcarbodiimide and a catalytic amount ofcopper (II) chloride. An equivalent amount of a carbodiimide means onemole of the carbodiimide for each mold of the Formula-VIIIa reactant. Toensure completeness of the reaction, it is advantageous to use an excessof the carbodiimide, i.e., 1.5 to 5 or even more equivalents of thecarbodimide.

The dehydration is advantageously carried out in the presence of aninert organic diluent which gives a homogeneous reaction mixture withrespect to the Formula-VIIIa reactant and the carbodiimide. Diethylether is a suitable diluent.

It is advantageous to carry out the dehydration in an atmosphere of aninert gas, e.g., nitrogen, helium, or argon.

The time required for the dehydration will depend in part on thereaction temperature. With the reaction temperature in the range 20 to30 C the dehydration usually takes place in about 40 to 60 hours.

The Formula-Xa product is isolated by methods known in the art, e.g.,filtration of the reaction mixture and evaporation of the filtrate. Theproduct is then purified by methods known in the art, advantageously bychromatography on silica gel.

The conversion of Formula-VIIa and Formula-Xa compounds to Formula XIacompounds is effected with base as described above in connection withCharts A and A-l.

The formula VIII and X compounds produced according to the processesoutlined in Charts B, C, and D and discussed above are all carboxylicacid esters, wherein R is not hydrogen. Moreover, when these compoundsare used to produce compounds of formulas IX and XI according to theprocesses outlined in Chart A and discussed above, corresponding Resters are likely to be produced, especially in the case of the PGFcompounds of formulas IX. For some of the uses described above, it ispreferred that these formula VIII to XI componds be in free acid form,or in salt form which requires the free acid as a starting material. Itis also sometimes desirable to have the free acid or salt forms of theacetylenic compounds of the 5,6,17,18- dehydro-PGE -type (VIId) and the5,6,17,18-dehydroPGA -type (Xd) compounds, as well as the5,6,17,l8-dehydro-PGF -type (IXd) and 5,6,17,18- dehydro-PGB -type (XId)compounds and which are derivable therefrom by the processes outlined inChart A- l because these free acids and salt forms have properties likethose of the corresponding hydrogenated (olefinic) compounds and areuseful for the same purposes detailed above.

The formula IXe, XIe, IXd, and XId R -esters are easily hydrolyzed orsaponified by the usual known procedures, especially when R is alkyl ofone to 4 carbon atoms, inclusive. Therefore it is preferred when thefree acid form of compounds IXe, XIe, IXd, and XId is desired, that R,by such alkyl, especially methyl or ethyl.

On the other hand, the formula VIIIe, Xe, VIIId, and Xd products aredifficult to hydrolyze or saponify without unwanted structural changesin the desired acids.

36 There are two other procedures useful to make the free acid form offormula VIIIe, Xe, VIIId, and Xd prod ucts.

One of those procedures is applicable mainly in preparing the free acidsfrom the corresponding alkyl esters wherein the alkyl group contains oneto 8 carbon atoms, inclusive. That procedure comprises subjecting thealkyl ester corresponding to formula VIIIe, Xe, VI- IId, or Xd to theacylase enzyme system of a microorganism species of Subphylum 2 ofPhylum III, and thereafter isolating the acid. Especially preferred forthis purpose are species of the orders Mucorales, Hypocreales,Moniliales, and Actinomycetales. Also especially preferred for thispurpose are the species of the families Mucoraceae, Cunninghamellaceae,Nectreaceae, Moniliaceae, Dematiaceae, Tuberculariaceae,Actinomycetaceae, and Streptomycetaceae. Also especially preferred forthis purpose are species of the genera Absidia, Circinella, Gongronella,Rhizopus, Cunninghamella, Calonectria, Aspergillus, Penicillium,Sporotrichum, Cladosporium, Fusarium, Nocardia, and Streptomyces.

Examples of microorganisms falling within the scope of those p'referredorders, families, and genera are listed in U.S. Pat. No. 3,290,226 anddetails of the process are disclosed in German Offenlegunsschift No.1,937,678, reprinted in Farmdoc Complete Specifications, Book No. 13,No. 6863R, Week R5, Mar. 18, 1970.

This enzymatic ester hydrolysis is carried out by shaking the formulaVIIIe, Xe, VIIId, or Xd alkyl ester in aqueous suspension with theenzyme contained in a culture of one of the above-mentionedmicroorganism species until the ester is hydrolyzed. A reactiontemperature in the range 20 to 30 C. is usually satisfactory. A reactiontime of 1 to 20 hours is usually sufficient to obtain the desiredhydrolysis. Exclusion of air from the reaction mixture, for example,with argon or nitrogen is usually desirable.

The enzyme is obtained by harvest of cells from the culture, followed bywashing and resuspension of the cells in water, and cell disintegration,for example, by stirring with glass beads or by sonic or ultrasonicvibrations. The entire aqueous disintegration mixture is used as asource of the enzyme. Alternatively and preferably, however, thecellular debris is removed by centrifugation or filtration, and theaqueous supernatant or filtrate is used.

In some cases, it is advantageous to grow the microorganism culture inthe presence of an alkyl ester of an aliphatic acid, said acidcontaining 10 to 20 carbon atoms, inclusive, and said alkyl containingone to 8 carbon atoms, inclusive, or to add such an ester to the cultureand maintain the culture without additional growth for 1 to 24 hoursbefore cell harvest. Thereby, the enzyme produced is sometimes made moreeffec tive in transforming the formula VIIIe, Xe, VIIId, or Xd ester tothe free acid. An example of a useful alkyl ester for this purpose ismethyl oleate.

Although, as mentioned above, most of the R esters encompassed byformulas VIIIe, Xe, VIIId, and Xd are not easily hydrolyzed orsaponified to the corresponding free acids, certain of those esters aretransformed to free acids by another method. Those esters are thehaloethyl esters wherein R is CI-I CCl They are transformed to freeacids by treatment with zinc metal and an alkanoic acid of 2 to 6 carbonatoms, preferably acetic acid. Zinc dust is preferred as the physicalform of the zinc. Mixing the halo ethyl ester with the zinc dust atabout 25 C. for several hours usually causes substantially completereplacement of the haloethyl moiety of the formula VIIIe, Xe, VIIId, orXd ester with hydrogen. The free acid is then isolated from the reactionmixture by procedures known to the art. This procedure is alsoapplicable to the production of the free acid form of the formula IXe,XIe, IXd, and XId compounds from the corresponding haloethyl estersthereof.

As described above, the alkylation of cyclic ketone XV to ketone XXIII(Chart B) usually produces a mixture of alpha and beta alkylationproducts with respect to the CI-I -C E C-ACOOR or the moiety. Also asdescribed above, those two isomers lead to different final products,alpha leading to the PG -series and beta leading to the 8-iso-PG-series. If a compound in one or the other of those series is preferred,there are two methods for favoring production of the preferred finalproduct.

One of those methods involves isomerization of the final product offormula VIIIe or formula VIIId. Either the alpha isomer of formula VIIIeor VIIId, or the beta isomer of formula VIIIe or VIIId is maintained inan inert liquid 'diluent in the range to 80 C. and in the presence of abase characterized by its water solution having a pH below about 10until a substantial amount of the isomer has been isomerized to theother isomer, i.e., alpha to beta or beta to alpha. Preferred bases forthis purpose are the alkali metal salts of carboxylic acids, especiallyalkanoic acids of 2 to 4 carbon atoms,

e. g., sodium acetate. Examples of useful inert liquid diluents arealkanols of one to 4' carbon atoms, e.g., ethanol. This reaction atabout 25 C. takes about one to about 20 days. Apparently an equilibriumis established. The mixtures of the two isomers, alpha and beta, areseparated from the reaction mixture by known procedures, and then thetwo isomers are separated from each other by known procedures, forexample, chromatography, recrystallization, or a combination of those.The less preferred isomer is then subjected to the same isomerization toproduce more of the preferred isomer. In this manner, by repeatedisomerizations and seaprations, substantially all of the less preferredisomer of the formula VIIIe or formula VIIId compound is transformed tomore preferred isomer.

The second method for favoring production of a preferred final formulaVIIIe or formula VIIId isomer in- I volves any one of the intermediatesof formulas XVI, XXII, XXIII, XXIV, or XXV (Chart B). Either the alphaform or the beta form of one of those intermediates is transformed to amixture of both isomers by starting isomer has been isomerized to theother isomer. Preferred bases for this isomerization are alkali metalamides, alkali metal alkoxides, alkali metal hydrides, and triarylmethylalkali metals. Especially preferred are alkali metal tert-alkoxides of 4to 8 carbon atoms, e.g., potassium tert-butoxide. This reaction at about25 C. proceeds rapidly (one minute to several hours). Apparently anequilibrium mixture of both isomers is formed, starting with eitherisomer. The isomer mixtures in the equilibrium mixture thus obtained areisolated by known procedures, and then the two isomers are separatedfrom each other by known procedures, for example, chromatography. Theless preferred isomer is then subjected to the same isomerization toproduce more of the preferred isomer. In this manner, by repeatedisomerizations and separations,

substantially all of the less preferred isomer of any of theseintermediates is transformed to the more preferred isomer. u

The final formula VIIIe, IXe, Xe, and XIe compounds and VIIId, IXd, Xd,and XId compounds prepared by the processes of this invention, in freeacid form, are transformed to phannacologically acceptable salts byneutralization with appropriate amounts of the corresponding inorganicor organic base, examples of which correspond to the cations and amineslisted above. These transformations are carried out by a variety ofprocedures known in the art to be generally useful for the preparationof inorganic, i.e., metal or ammonium, salts, amine acid addition salts,and quaternary ammonium salts. The choice of procedure dependsin partupon the solubility characteristics of the particular salt to beprepared. In the case of the inorganic salts, it is usually suitableto'dissolve the acid in water containing the stoichiometric amount of ahydroxide, carbonate, or bicarbonate corresponding to the inorganic saltdesired. For example, such use of so- .dium hydroxide, sodium carbonate,or sodium bicarbonate gives a solution of the sodium salt. Evaporationof the water or addition of a water-miscible solvent of moderatepolarity, for example, a lower alkanol or a lower alkanone, gives thesolid inorganic salt if that form is desired.

To produce an amine salt, the fonnula VIIIe, IXe, Xe, XIe, VIIId, IXd,Xd, or XId acid is dissolved in a suitable solvent of either moderateorlow polarity. Examples of the fonner are ethanol, acetone, and ethylacetate. Examples of thelatter are diethyl ether and benzene. At least astoichiometric amount of the amine corresponding to the desired cationis then added to that solution. If the resulting salt does notprecipitate, it is usually obtained in solid form by addition of amiscible diluent of low polarity or by evaporation. If the amine isrelatively volatile, any excess can easily be removed by evaporation. Itis preferred to use stoichiometric amounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe formula VIIIe, IXe, Xe, XIe, VIIId, IXd, Xd, or XId acid with thestoichiometric amount of the corresponding quaternary ammonium hydroxidein water solution, followed by evaporation of the water.

The invention can be more fully understood by. the following examplesand preparations in which the parts are by weight and solvent ratios areby volume unless otherwise specified.

All temperatures are in degrees Centigrade.

NMR spectra are recorded on a Varian A-6O spectrophotometer ondeuterochloroform solutions with tetramethylsilane as an internalstandard (downfield).

Mass spectra are recorded on an Atlas CI-I-4. mass spectrometer with aTO-4 source (ionization voltage ev).

For convenience the formulas are given in the natural configuration, itbeing understood, though, that the compounds produced, unless otherwisespecified, include the enantiomorphs.

1. A RACEMIC MIXTURE OF A COMPOUND OF THE FORMULA:
 2. A racemic mixtureaccording to claim 1 wherein R1 is hydrogen or alkyl of one to 4 carbonatoms, inclusive, or a pharmacologically acceptable salt thereof when R1is hydrogen.
 3. A racemic mixture according to claim 2 wherein theside-chain hydroxy is in S configuration.
 4. A racemic mixture accordingto claim 3 wherein n is one.
 5. A racemic mixture according to claim 4wherein A is trimethylene.
 6. A racemic mixture according to claim 5wherein R2 is ethyl.
 7. Racemic PGF3 , a racemic mixture according toclaim 6 wherein R1 is hydrogen.
 8. AN OPTICALLY ACTIVE COMPOUND OF THEFORMULA:
 9. An optically active compound according to claim 8 whereinthe side-chain hydroxy is in S configuration, and wherein R1 is hydrogenor alkyl of one to 4 carbon atoms, or a pharmacologically acceptablesalt thereof when R1 is hydrogen.
 10. An optically active compoundaccording to claim 9 wherein R2 is ethyl and b is one.
 11. An opticallyactive compound according to claim 10 wherein Z is ethylene substitutedwith 2 fluoro on the carbon atom alpha to the carboxylate function. 12.An optically active compound according to claim 11 wherein R3 and R4 arehydrogen.
 13. An optically active compound according to claim 11 whereinR3 is alkyl of one to 4 carbon atoms, inclusive, and R4 is hydrogen.